title: Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.
abstract: Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used quantitative, mass spectrometry-based metabolic profiling to investigate the fed-to-fasted transition in PPARalpha(+/+) and PPARalpha(-/-) mice. Compared to PPARalpha(+/+) animals, acylcarnitine profiles of PPARalpha(-/-) mice revealed 2- to 4-fold accumulation of long-chain species in the plasma, whereas short-chain species were reduced by as much as 69% in plasma, liver, and skeletal muscle. These results reflect a metabolic bottleneck downstream of carnitine palmitoyltransferase-1, a mitochondrial enzyme that catalyzes the first step in beta-oxidation. Organic and amino acid profiles of starved PPARalpha(-/-) mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPARalpha(-/-) mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice. In summary, comprehensive metabolic profiling revealed novel biomarkers of defective fat oxidation, while also highlighting the potential value of supplemental carnitine as a therapy and diagnostic tool for metabolic disorders.
authors.affiliation: Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Weibing
authors.initials: W
authors.lastname: Xing
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
mesh_terms: D000215:Acylation; D000284:Administration, Oral; D000596:Amino Acids / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D002331:Carnitine / Q000008:administration & dosage* / Q000378:metabolism*; D006706:Homeostasis; D006358:Hot Temperature; D008297:Male; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D047493:PPAR alpha; D002331:Carnitine